Novel MEK inhibitor trametinib and other retinoblastoma gene (RB)-reactivating agents enhance efficacy of 5-fluorouracil on human colon cancer cells
Novel MEK inhibitor trametinib and other retinoblastoma gene (RB)-reactivating agents enhance efficacy of 5-fluorouracil on human colon cancer cells
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DOI：
10.1111/cas.12139
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发表时间：
2013-06-01
期刊：
影响因子：
5.7
通讯作者：
Sakai, Toshiyuki
中科院分区：
文献类型：
--
作者：
Watanabe, Motoki;Sowa, Yoshihiro;Sakai, Toshiyuki
随着分子靶向药物的出现，结直肠癌的化疗变得更加复杂和多样化。5-氟尿嘧啶（5-FU）一直是结直肠癌化疗的主要药物，但5-FU与新型分子靶向药物联合应用是否有效仍是未知数。胸苷酸合成酶（TS）是5-FU的直接靶点，低水平的TS通常被认为是5-FU疗效的增敏因素。因此我们推测，RB激活剂可以增强5-FU的疗效，因为RB激活剂可以抑制TS基因启动子转录因子E2 F的功能。我们使用了三种RB再活化剂，曲美替尼/GSK 1120212（MEK抑制剂），非诺贝特（PPAR激动剂）和LY 294002（PI 3 K抑制剂），与5-FU一起对抗人结肠癌HT-29和HCT 15细胞。曲美替尼诱导HT-29细胞中p15和p27表达，并降低细胞周期蛋白D1水平。非诺贝特还使HT-29细胞中ERK 1/2去磷酸化并降低细胞周期蛋白D1水平。LY 294002诱导HCT 15细胞p27表达。所有三种药物引起RB蛋白去磷酸化和G1期阻滞，TS表达减少。因此，5-FU与每种药剂的组合导致HT-29或HCT 15细胞中的集落数量显著减少。这些结果表明，使用分子靶向药物的RB-再激活疗法是基于5-FU的化疗的新策略。特别是，我们强烈期望在日本发现并最近提交给FDA批准的曲美替尼与结直肠癌的既定方案一起使用。
Chemotherapy for colorectal cancer has become more complicated and diversified with the appearance of molecular-targeting agents. 5-Fluorouracil (5-FU) has been a mainstay of chemotherapy for colorectal cancer, but it is still unknown whether the combining of 5-FU with novel molecular-targeting agents is effective. Thymidylate synthase (TS) is a direct target of 5-FU, and the low TS level has been generally supposed to sensitize 5-FU's efficacy. We therefore hypothesized that RB-reactivating agents could enhance the efficacy of 5-FU, because the RB-reactivating agents could suppress the function of transcription factor E2F of TS gene promoter. We used three RB-reactivating agents, trametinib/GSK1120212 (MEK inhibitor), fenofibrate (PPAR agonist), and LY294002 (PI3K inhibitor), with 5-FU against human colon cancer HT-29 and HCT15 cells. Trametinib induced p15 and p27 expression and reduced cyclin D1 levels in HT-29 cells. Fenofibrate also dephosphorlated ERK1/2 and reduced cyclin D1 levels in HT-29 cells. LY294002 induced p27 expression in HCT15 cells. All three agents caused dephosphorylation of RB protein and G1-phase arrest with a reduction of TS expression. As a consequence, the combination of 5-FU with each of the agents resulted in a significant decrease of colony numbers in HT-29 or HCT15 cells. These results suggest RB-reactivation therapy using molecular-targeting agents to be a new strategy for 5-FU-based chemotherapy. In particular, we strongly expect trametinib, which was discovered in Japan and was recently submitted to FDA for approval, to be used together with established regimens for colorectal cancer.